A Pilot Randomized Controlled Trial of Maternal Oxygen Therapy for Fetal Left Heart Hypoplasia

Birth defects are the leading cause of infant mortality in the United States, and congenital heart disease is the leading cause of birth-defect related infant mortality. Despite advances, conditions related to left heart hypoplasia (LHH) are the most severe, and contribute significantly to this overall mortality as well as morbidity, including delayed brain maturation.

Conditions involving left heart hypoplasia (LHH) are among the most severe, and contribute significantly to this overall mortality. Sequelae are not limited to mortality, as recurrent interventions and impaired neurodevelopmental outcomes are highly prevalent among survivors with LHH. During the last 15 years, fetal cardiac intervention (FCI) has been introduced as a novel treatment for these children. The potential to halt disease progression in utero and to avoid or reduce the complexity of future surgery is very alluring. Current FCI is highly invasive, and there is limited and controversial data pertaining to efficacy, risk, and criteria for intervention. There is also a group of fetuses with LHH who require neonatal intervention, which may include single ventricle palliation, but are not candidates for current FCI.

The investigators intend to use a pilot study design to evaluate a novel non-invasive FCI to improve left heart growth in the fetus with LHH. The intervention will be chronic administration of supplemental oxygen provided to pregnant subjects (maternal hyperoxygenation, MH) compared to subjects not undergoing MH. Currently, two FCIs are available for left-sided disease, both of which are invasive and carry significant risk. The interventions include aortic valvuloplasty for aortic stenosis and atrial septoplasty/stenting for hypoplastic left heart syndrome with a restrictive or intact atrial septum. While there is tremendous enthusiasm for these procedures, there is limited and controversial data pertaining to efficacy, risk, and inclusion criteria for intervention.

There is also a further group of patients with LHH without frank aortic stenosis but hypoplasia of multiple left heart structures. While these patients almost universally require neonatal intervention which may include single ventricle palliation, they are not candidates for the fetal interventions currently available. This is the population of fetuses that we intend to target. The etiologies of left heart obstruction are unknown, although the common pathway is thought to be diminished blood flow to left heart structures in utero. Hypothesized etiologies include abnormal or restricted PFO flow, reduced flow across the mitral valve atrial septal aneurysm, low aortic flow due to aortic valvar abnormalities, presence of a ventricular septal defect, or subaortic narrowing. In the fetus, maternal blood with the highest oxygen and glucose concentration is delivered via the umbilical, and travels via the ductus venosus to the right atrium, where the majority crosses the foramen ovale and passes to the left heart. Most of that blood is used to perfuse the developing brain. In the normal fetal heart, about 10% of the left heart output, rather than traveling to the cerebral circulation, passes through the aortic isthmus and joins the blood that will perfuse the lower body. The low volume of blood flow through the fetal lungs is due to high pulmonary vascular resistance. The fetal pulmonary circulation is very sensitive to small changes in pulmonary arterial oxygen saturation and tension. Pulmonary vascular responses to changes in oxygen levels are very much related to gestational age and this sensitivity increases dramatically with advancing gestational age in the fetus.

It has been shown in both fetal sheep and human fetuses that when supplemental oxygen is provided to gravid mothers, there is evidence of an increase in fetal pulmonary blood flow, and this response becomes more pronounced late in gestation. This increase in pulmonary blood flow results in greater blood flow to the left atrium, and potentially to the left ventricle and across the aorta.